Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to different drugs (active pharmaceutical ingredients) and certain forms of said drugs, such as stereoisomers, salts and/or polymorphs thereof.
• the present invention covers various aspects that are munbered (i), (ii), (iii), (iv), (v), (vi) and (vii). Aspects (i), (ii), (iii), (iv), (v), (vi) and (vii) are separate from one another.
• the present invention relates to
• aspects (i) of the invention concerns forms of ⁇ drug1 ⁇ , especially salts of ⁇ drug1 ⁇ , and relates to administration units comprising fumarate, maleate, chloride, phosphate, succinate or malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, i.e. ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , and ⁇ drug1f ⁇ , respectively.
• the invention relates to a solid form of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, namely to fumarate, maleate, chloride, phosphate, succinate or malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, which is useful for treating prevention, treatment of a disease, in which nAChR ct7 activation plays a role, revention, treatment of of psychiatric or neurodegenerative disorders, CNS, PNS diseases, and inflammation.
• WO2013010916 contains the following information concerning the fumarate, maleate, chloride, phosphate, succinate and malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane: 1.
• the salt of the invention is the fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.
• the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form may be produced from isopropyl alcohol when one equivalent fumaric acid is used.
• the molecular formula is C 23 H 26 N 2 O 5 . It shows good solubility in aqueous media (>30mg/ml in water, 0.1 N Hcl, and pH 6.8 buffer). It is slightly hygroscopic: Loss on drying (LOD) of a sample was ⁇ 0.03% and moisture gain was 0.5% at 85% relative humidity (RH).
• XRPD X-ray powder diffraction
• the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 theta (2 ⁇ ) of 3.8, 13.7, 15.2, 17.4, 19.8 and 20.1,
• the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1 of WO2013010916 .
• the term "substantially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2°.
• the salt of the invention is the maleate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, e.g. the mono-maleate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.
• the mono-maleate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form may be produced from acetonitrile when one equivalent maleic acid is used. It shows good solubility in aqueous media (>30mg/ml in water, 0.1NHCl, and pH 6.8 buffer). It is slightly hygroscopic: LOD of a sample was ⁇ 0.03% and moisture gain was 0.3% at 85% RH. Its melting point was determined by heating at 2°C/minute to be 152-154°C (onset) with subsequent decomposition. It shows good stability in many buffer solutions and at various pH values.
• the solid-state stability is good.
• the mono-maleate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 theta (2 ⁇ ) of 12.9, 16.0, 18.0, 19.1
• the mono-maleate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 2 of WO2013010916 .
• the salt of the invention is the hydrochloride salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, e.g.
• the mono-hydrochloride salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form may be produced directly from a synthesis mixture by adding hydrochloric acid. It shows good solubility in aqueous media (>30mg/ml).
• the mono-hydrochloride salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 theta (2 ⁇ ) of 7.3, 11.6, 17.2, 18.4, 20.8 and 31.1, ⁇ 0.2, respectively.
• the mono-hydrochloride salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 3 of WO2013010916 .
• the salt of the invention is the phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, e.g.
• Form A of the mono-phosphate salt A mono-phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline fomi may be produced from ethanol when one equivalent phosphoric acid is used.
• the mono-phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)- 1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 theta (2 ⁇ ) of 4.7, 14.3, 16.5, 17.7, 18.2 and 19.7, ⁇ 0.2, respectively.
• the mono-phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 4A of WO2013010916 .
• Form A of the mono-phosphate salt shows good solubility in aqueous media (>30mg/ml). It is slightly hygroscopic: when tested, LOD of a sample was about 0.5% and moisture gain was 0.2% at 85% RH. Its melting/decomposition point was determined by heating at 2°C/minute to be about 222°C. 4.2.
• Form B of the phosphate salt Another form of the phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline fomi (Form B of the phosphate salt) was found as described in the Examples section (see Example 4.2 of WO2013010916 ). The associated XRPD pattern is shown in Figure 4B of WO2013010916 . Summary of XRPD pattern: No. 2 theta (deg°) Intensity No.
• Form C of the phosphate salt Another form of the phosphate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form (Form C of the phosphate salt) was found as described in the Examples section (see Example 4.3 of WO2013010916 ).
• the associated XRPD pattern is shown in Figure 4C of WO2013010916 . Summary of XRPD pattern: No. 2 theta (deg°) Intensity No.
• the salt of the invention is the succinate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, e.g.
• the mono-succinate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 theta (2 ⁇ ) of 10.7, 15.2, 15.8, 17.4, 19.4 and 23.7, ⁇ 0.2, respectively.
• the mono-succinate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 5A of WO2013010916 .
• Form A of the the mono-succinate salt shows good solubility in aqueous media (2-15mg/ml). It is considered to be a mono-hydrate: when tested, LOD of a sample was about 4.5%. Theoretically, an amout of 4.1 % water correlates to 1 water molecule per salt molecule. Moisture gain was 0.3% at 85% RH.
• Form B of the mono-succinate salt Another form of the succinate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form (Form B of the mono-succinate salt) was found as described in the Examples section (see Example 5.3 of WO2013010916 ).
• the associated XRPD pattern is shown in Figure 5B of WO2013010916 . Summary of XRPD pattern: No. 2 theta (deg°) Intensity No.
• the salt of the invention is the malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane, e.g.
• the mono-malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form may be produced from acetonitrile when one equivalent malonic acid is used. It shows good solubility in aqueous media (>30mg/ml). It is slightly hygroscopic: when tested, LOD of a sample was 0% and moisture gain was 1.3% at 85% RH.
• the mono-malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern with at least four, more preferably five, most preferably all of the following peaks at an angle of refraction 2 thet
• the mono-malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 6 of WO2013010916 .
• Preparation methods for crystalline forms Crystalline fomis may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying.
• Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
• High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs. Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999 ).
• solvent for crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent.
• Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.
• An antisolvent is a solvent in which the compound has low solubility.
• a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
• slurry means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.
• Seed crystals may be added to any crystallization mixture to promote crystallization (see “ Programmed Cooling of Batch Crystallizers,” J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377 ). In general, seed crystals of small size are used. Seed crystals of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions.
• a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form.
• the isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product.
• the resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
• the product may be delumped by sieving or forced sieving, if necessary.
• Crystalline forms may be prepared directly from the reaction medium of the final process for preparing (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane or a salt of the invention. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which the salt of the invention may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
• the presence of more than one polymorph in a sample may be determined by techniques such as powder x-ray diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy.
• PXRD powder x-ray diffraction
• solid state nuclear magnetic resonance spectroscopy For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample.
• the simulated PXRD may be calculated from single crystal x-ray data; see Smith, D.K., UA FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).
• mean particle size (X5o) refers to a crystal size distribution wherein 50% of crystals related to the total volume of particles have a smaller diameter of an equivalent sphere than the value given.
• X90 refers to a crystal size distribution wherein 90% of crystals related to the total volume of particles have a smaller diameter of an equivalent sphere than the value given.
• X10 refers to a crystal size distribution wherein 10% of crystals related to the total volume of particles have a smaller diameter of an equivalent sphere than the value given.
• one embodiment of the invention is a method of preparing a mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form comprising the steps of
• the mean particle size of the seed crystals is from 1 ⁇ i ⁇ i to 10 ⁇
• the seed crystals are added in an amount of from 0.08% to 2% of the amount of the salt in step (a).
• One embodiment of the invention is a method of preparing a mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form comprising the steps of
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is at least 15 ⁇ i ⁇ i.
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is at least 20 pm.
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is at least 25 pm.
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is from 20 pm to 35 pm.
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is from 20 pm to 35 pm; the X10 is from 3 pm to 10 pm; and the X90 is from 70 pm to 90 pm.
• One further embodiment of the invention is mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form, wherein the mean particle size of the crystals is from 25 pm to 30 pm.
• the solid form of a salt of the invention may be characterized using various techniques, the operation of which are well known to those of ordinary skill in the art.
• the forms may be characterized and distingushed using single crystal x-ray diffraction, which is based on unit cell measurements of a single crystal of the form at a fixed analytical temperature.
• a detailed description of unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3.
• the unique arrangement of atoms in spatial relation within the crystalline lattice may be characterized according to the observed fractional atomic coordinates.
• Another means of characterizing the crystalline structure is by powder x-ray diffraction analysis in which the diffraction profile is compared to a simulated profile representing pure powder material, both run at the same analytical temperature, and measurements for the subject form characterized as a series of 3 ⁇ values (usually four or more).
• Other means of characterizing the form may be used, such as solid state nuclear magnetic resonance (NMR), differential scanning calorimetry, thermography and gross examination of the crystalline or amorphous morphology. These parameters may also be used in combination to characterize the subject form.
• NMR solid state nuclear magnetic resonance
• thermography thermography
• Gross examination of the crystalline or amorphous morphology thermography
• Mean particle sizes, X90 and X10 are typically measured by Fraunhofer light diffraction.
• Reference Example A1 Preparation/Characterization of free base of (R)-3-(6-(4- methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane in crystalline form
• Form A About 8mg of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane in free base form dissolved in 0.2ml methanol was dried in vacuum at 40°C for >5hours.
• Form A shows low solubility in aqueous media (0.05mg/ml). It is hygroscopic: when tested, Loss on drying (LOD) of a sample was 0.1% and moisture gain was 2% at 93% relative humidity (RH). Its melting point was determined by heating at 2°C/minute to be 106°C (onset) with subsequent decomposition.
• LOD Loss on drying
• Reference Example A2 Preparation/Characterization of free base of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.21octane in crystalline form
• Form B About 8mg of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-azabicyclo[2.2.2]octane in free base form dissolved in 0.2ml methanol was dried in vacuum at 40°C for >5hours. After drying, ethanol was added to the solid residue and the mixture was heated to 40°C and vortexed for about 2hours.
• Example 1 Preparation of mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)- 1-aza-bicvclof2.2.21octane in crystalline form: 500 mg of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form were suspended in 20 ml isopropyl alcohol. A stochtometric amount of fumaric acid was added. The resulting solution was stirred at ambient temperature for 14 hours. The precipitate was collected by filtration and analyzed by proton-N R and XRPD (see Figure 1 of WO3013010916 ).
• Example 1.1 Preparation of mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3- yloxy)-1-aza-bicyclo[2.2.21octane in crystalline form by seeded crystallization:
• the salts of the invention exhibit valuable pharmacological properties administered to animals/humans, and are therefore useful as pharmaceuticals.
• Salts of the invention are selective 7-nAChR partial agonists. Due to their pharmacological profiles, salts of the invention are anticipated to be useful for the treatment of diseases or conditions as diverse as CNS related diseases, PNS related diseases, diseases related to inflammation, pain and withdrawal symptoms caused by an abuse of chemical substances.
• Diseases or disorders related to the CNS include general anxiety disorders, cognitive disorders, learning and memory deficits and dysfunctions, Alzheimer's disease (AD), prodromal AD, mild cognitive impairment in the elderly (MCI), amnestic MCI, age associated memory impairment, attention deficit and hyperactivity disorder (ADHD), Parkinson's disease, L-dopa induced dyskinesias associated with Parkinson's disease, Huntington's disease, ALS, prionic neurodegenerative disorders such as Creutzf eld- Jacob disease and kuru disease, Gilles de la Tourette's syndrome, psychosis, depression and depressive disorders, mania, manic depression, schizophrenia, the cognitive deficits in schizophrenia, obsessive compulsive disorders, panic disorders, eating disorders, nociception, AIDS-dementia, senile dementia, mild cognitive dysfunctions related to age, autism, dyslexia, tardive dyskinesia, epilepsy, and convulsive disorders, post-traumatic stress disorders, transient anoxia, pseudodementia, premenstru
• salts of the invention maybe useful for the treatment of endocrine disorders, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias as well as angina pectoris, hyperkinesia, premature ejaculation and erectile difficulty.
• salts of the invention may be useful in the treatment of inflammatory disorders ( Wang et al., Nature 2003, 421, 384 ; de Jonge et al., Nature Immunology 2005, 6, 844 ; Saeed et al., JEM 2005, 7, 11 13 ), disorders or conditions including inflammatory skin disorders, rheumatoid arthritis, post-operative ileus, Crohn's disease, inflammatory bowel disease, ulcerative colitis, sepsis, fibromyalgia, pancreatitis and diarrhoea. Salts of the invention may further be useful for the treatment of withdrawal symptoms caused by termination of the use of addictive substances, like heroin, cocaine, tobacco, nicotine, opioids, benzodiazepines and alcohol.
• addictive substances like heroin, cocaine, tobacco, nicotine, opioids, benzodiazepines and alcohol.
• salts of the invention may be useful for the treatment of pain, e.g. caused by migraine, postoperative pain, phantom limb pain or pain associated with cancer.
• the pain may comprise inflammatory or neuropathic pain, central pain, chronic headache, pain related to diabetic neuropathy, to post therapeutic neuralgia or to peripheral nerve injury.
• degenerative ocular disorders which may directly or indirectly involve the degeneration of retinal cells, including ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age-related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macular edema (CME), retinal detachment, retinitis pigmentosa, Stargardt's disease, Best's viteiiiform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degenerations, pathologic myopia, retinopathy of prematurity, and Leber's hereditary optic neuropathy.
• ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age-related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macular
• the salts of the invention can be combined with at least one compound selected from the group consisting of (a) conventional antipsychotics and (b) atypical antipsychotics, in which the antipsychotic is present in free form or in the form of a pharmaceutically acceptable salt; for simultaneous, separate or sequential use to treat psychiatric disorders.
• psychiatric disorders includes, but is not limited to schizophrenia, anxiety disorders, depression and bipolar disorders.
• the psychiatric disorder is schizophrenia, more preferably schizophrenia which is refractory to monotherapy employing one of the combination partners alone.
• conventional antipsychotics includes, but is not limited to haloperidol, fluphenazine, thiotixene and flupentixol.
• typical antipsychotics includes, but is not limited to clozaril, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazol.
• the salts of the invention are useful in the treatment of the above diseases/conditions.
• the invention also relates to a salt of the invention (e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form) for use as a medicament.
• a salt of the invention e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form
• the invention also relates to a salt of the invention (e.g.
• the invention also relates to the use of a salt of the invention (e.g.
• the invention also relates to the use of a salt of the invention (e.g.
• the invention also relates to a method for the prevention, treatment and / or delay of progression of a disease or condition, in which 7-nAChR activation plays a role or is implicated, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a salt of the invention (e.g.
• the invention relates to a method for the prevention, treatment and / or delay of progression of a psychiatric or neurodegenerative disorder in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a salt of the invention (e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form).
• a salt of the invention e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.
• the invention relates to a method for the prevention, treatment and / or delay of progression of a disease or condition, in which a7-nAChR activation plays a role or is implicated, in a subject in need thereof, which comprises (i) diagnosing said disease or condition in said subject and (ii) administering to said subject a therapeutically effective amount of a salt of the invention (e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form).
• a salt of the invention e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form.
• the invention in another embodiment, relates to a method for the prevention, treatment and / or delay of progression of a psychiatric or neurodegenerative disorder, in a subject in need thereof, which comprises (i) diagnosing said disorder in said subject and (ii) administering to said subject a therapeutically effective amount of a salt of the invention (e.g. the mono-fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in crystalline form).
• Treatment may comprise a reduction in the characteristics associated with the disease, condition or disorder, including, although not limited to, e.g.
• the salt of the invention may be used to delay or prevent the onset of the Instant Movement Disorder.
• subject refers preferably to a human being, especially to a patient being diagnosed with the the disease, condition or disorder.
• therapeutically effective amount typically refers to a drug amount which, when administered to a subject, is sufficient to provide a therapeutic benefit, e.g. is sufficient for treating, preventing or delaying the progression of the disease, condition or disorder (e.g. the amount provides an amelioration of symptoms, e.g.
• the appropriate dosage will vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, preferably from about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg.
• an indicated daily dosage is in the range from about 0.1 to about 1000 mg, preferably from about 1 to about 400 mg, most preferably from about 3 to about 100 mg of a salt of the invention conveniently administered, for example, in divided doses up to four times a day.
• Amorphous forms/crystalline forms of salts of the invention are useful as intermediates for preparing crystalline forms/other crystalline forms of salts of the invention that are useful in the treatment of the above diseases/conditions.
• the invention relates to an administration unit comprising fumarate, maleate, chloride, phosphate, succinate or malonate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to prevention, treatment of a disease, in which nAChR ct7 activation plays a role, revention, treatment of of psychiatric or neurodegenerative disorders, CNS. PNS diseases, and inflammation.
• aspects (ii) of the invention concerns formulations of ⁇ drug2+drug3 ⁇ , especially formulations of ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ , and relates to administration units comprising pharmaceutical form of a combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol 3-Kinase (PBKinase) inhibitor.
• Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are described in, for example, WO2007140222 and WO2010020675 , which are hereby incorporated by reference in entirety.
• Phosphatidylinositol 3-Kinase (PBKinase) inhibitors are described in, for example, WO2004048365 , WO2007084786 , WO2004096797 , WO2010029082 , WO2006122806 which is hereby incorporated by reference in entirety.
• the invention relates to a form of a combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol 3-Kinase (PBKinase) inhibitor, namely to pharmaceutical form of a combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol 3-Kinase (PBKinase) inhibitor, which is useful for treating solid tumors and hematological malignancies, breast cancer, endometrium cancer, urinary track cancer, melanoma, colon cancer, stomach cancer, cervical cancer, prostate cancer and ovarian cancer.
• CDK4/6 cyclin dependent kinase 4/6
• PBKinase Phosphatidylinositol 3-Kinase
• CDK4/6 cyclin dependent kinase 4/6
• PBKinase Phosphatidylinositol 3-Kinase
• a combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol 3-Kinase (PBKinase) inhibitor is a combination with (as described in W03013006533 and cited here) in one embodiment, the first agent that inhibits the CDK4/6 pathway is ⁇ drug2a ⁇ which is 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide or pharmaceutically acceptable salt(s) thereof.
• ⁇ drug2a ⁇ is described by Formula A: or pharmaceutically acceptable salt(s) thereof.
• the second agent that inhibits PB Kinase is ⁇ drug3a ⁇ described by Formula B1 : or pharmaceutically acceptable salt(s) thereof.
• ⁇ drug3a ⁇ has been described with several names, such as 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine; 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin2-ylamine; 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine; or CAS name 5-(2,6-di-4-morpholinyl-4-pyrimidinyl) -4- (trifluoromethyl)-2-pyrimidinamine.
• the second agent that inhibits PI3 Kinase is ⁇ drug3b ⁇ described by Formula B2: or pharmaceutically acceptable salt(s) thereof.
• ⁇ drug3b ⁇ is known as (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-( ⁇ 4-methyl-5-[2-(2,2,2-trit1uoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide).
• W03013006533 describes and which is incorporated by reference and also preferred here as cited:
• W03013006533 discloses the following examples:
• the invention relates to an administration unit comprising pharmaceutical form of a combination of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a Phosphatidylinositol 3-Kinase (PBKinase) inhibitor.
• CDK4/6 cyclin dependent kinase 4/6
• PBKinase Phosphatidylinositol 3-Kinase
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to solid tumors and hematological malignancies, breast cancer, endometriun cancer, urinary track cancer, melanoma, colon cancer, stomach cancer, cervical cancer, prostate cancer and ovarian cancer.
• aspects (iii) of the invention concerns formulations of ⁇ drug4 ⁇ , especially formulations of ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ , and relates to administration units comprising ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate.
• the invention relates to a solid form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydropyran-4-yl)-methanone, namely to ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate, which is useful for treating PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases,
• PI3K-mediated is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus ery
• haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
• systemic lupus erythematosus polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
• endocrine opthalmopathy Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an
• autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idio-pathic sprue
• autoimmune haematological disorders including e.g. hemolytic
• ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
• endocrine ophthalmopathy Graves' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior, intermediate and posterior as well as panuveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
• idiopathic nephro-tic syndrome or minimal change nephropathy tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dyslipidemia; conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia, Schnitzler syndrome, Waldenstrom's macroglobulinemia, angioedema,
• ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate is a form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone that may be characterized as follows:
• the term "form of the invention” refers to a crystalline anhydrous form, a crystalline solvate form or a salt form including a crystalline salt form of ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl ⁇ -(tetrahydro-pyran-4-yl)-methanone.
• Example 1 1 part of Example 1 (eg. 100 mg) is mixed with 5 parts of acetonitrile (0.5 ml. for each 100 mg of compound) with stirring. A solution is obtained by heating up to 40-60°C. The mixture is then allowed to slowly cool down to RT. After further cooling overnight (5°C), precipitation is observed. In case no precipitation is not observed, the volume of ethanol can be reduced using a nitrogen stream and repeating the overnight cooling step. The mixture is centrifuged to remove the ethanol. The solid is dried under vacuum at 25°C and 70 mbar. A crystalline anhydrous form of Example 1 with a MP of 131 °C is obtained.
• acetonitrile 0.5 ml. for each 100 mg of compound
• This crystalline form is also observed under other methods and/or solvents, such as heating and cooling in ethanol, acetone, ethyl acetate, isopropanol, by slurry in heptane, or by antisolvent addition in THF or 3-methyl-1-butanol using heptane as antisolvent.
• solvents such as heating and cooling in ethanol, acetone, ethyl acetate, isopropanol, by slurry in heptane, or by antisolvent addition in THF or 3-methyl-1-butanol using heptane as antisolvent.
• Example 1 Slurry of Example 1 in water e.g., 1 part of Example 1 in 10 parts of water, at RT produces a trihydrate form of Example 1.
• the crystals were separated by centrifugation and dried at room environment.
• Example 1 0.5 g of Example 1 (assay 91 .8%) are dissolved in 5 mL of methylethylketone and 0.25 mL of water and heated at 60°C. 213 mg of citric acid are added at 50°C and the mixture is allowed to cool down to RT within 30 min. Crystallization occurs at 45°C. The mixture is stirred for 16 h at RT. The crystals are collected by filtration. The filter cake is washed 3 times with 1 mL of methylethylketone and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum.
• Elementary analysis of the citrate salt shows a 1 :1 (monohydrate) form.
• Example 1 (assay 91.8%) are dissolved in 15 mL of acetonitrile and 0.2 mL of water and heated at 76°C. 129 mg of fumaric acid are added at 60°C. The solution is allowed to cool down to RT within 30 min. The salt precipitates and the suspension is stirred for 16 h at RT. The crystals are collected by filtration. The filter cake is washed 3 times with 1 mL of acetonitrile and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum.
• Elementary analysis of the fumarate salt shows a 1 :1 (monohydrate) form.
• Example 1 (assay 91.8%) are dissolved in 5 mL of ethanol absolute and 0.25 mL of water at 60°C. 250 mg of naphthalendisulfonic acid are added at 50°C and the mixture is allowed to cool down to RT within 30 min. Crystallization occurs at 40°C. The mixture is stirred for 16 h at RT. The crystals are collected by filtration. The filter cake is washed 3 times with 1 mL of ethanol and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum.
• Elementary analysis of the napadisylate salt shows a 2:1 (monohydrate) form.
• the invention relates to an administration unit comprising ⁇ (S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors; conditions, diseases or disorders in which one or more of the functions of B cells such as antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic r
• PI3K-mediated is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus ery
• haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
• systemic lupus erythematosus polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
• endocrine opthalmopathy Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an
• autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody- associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idio-pathic sprue
• autoimmune haematological disorders including e.g. hemolytic
• ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
• endocrine ophthalmopathy Graves' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior, intermediate and posterior as well as panuveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
• idiopathic nephro-tic syndrome or minimal change nephropathy tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dyslipidemia; conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia, Schnitzler syndrome, Waldenstrom's macroglobulinemia, angioedema,
• aspects (iv) of the invention concerns formulations of ⁇ drug5 ⁇ , especially formulations of ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ , and relates to administration units comprising 1- ⁇ (S)-3-[6-(6-Methoxy-5-tritluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl]-propan-1-one citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate.
• the invention relates to a solid form of 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl]-propan-1-one, namely to 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl]-propan-1-one citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate, which is useful for treating PI3K-related diseases including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancer
• PI3K-mediated is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus ery
• haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
• systemic lupus erythematosus polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
• endocrine opthalmopathy Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an
• autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idiopathic sprue
• autoimmune haematological disorders including e.g. hemolytic
• ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
• endocrine ophthalmopathy Graves' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior, intermediate and posterior as well as panuveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
• idiopathic nephro-tic syndrome or minimal change nephropathy tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dyslipidemia; conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia, Schnitzler syndrome, Waldenstrom's macrogloblulinemia, angioedema,
• 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]pyrrolidin-1-yl]-propan-1-one citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate is a form of 1- ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1yl ⁇ -propan-1-one that may be characterized as follows:
• the reaction mixture is partitioned between water (300 mL) and isopropyl acetate (100 mL) and the upper organic phase is discarded.
• the aqueous phase is partitioned between 25% NaOH (aq) (200 g) and 3-Me-THF (200 mL), and the organic phase is collected and dried.
• Triethylamine (16.32 mL, 1 17.48 mmol) is added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0 °C.
• the resulting mixture is stirred at 0 °C for 1 h.
• the reaction mixture is washed with water (1 10 mL) and the resulting organic phase is concentrated in vacuo to give a brown gum.
• hippuric acid (0.888 mmol) are added at 70°C.
• the solution is allowed to cool down to rt within 30 min. Crystallization occurs at 40°C.
• the suspension is stirred for 16 h at rt.
• the crystals are collected by filtration.
• the filter cake is washed 3 times with 1 mL of acetonitrile and afterwards dried for 16 h at 50°C and ca. 10 mbar vacuum.
• Elementary analysis of the hippurate salt shows a 1 :1 (waterless) form.
• Example 67 1 - ⁇ (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl]-propan-1-one: To a solution of (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1 -carboxylic acid tert-butyl ester (intermediate 24) (13.4 g, 27.1 mmol) in CH 2 CI 2 (100 mL), was added TFA (41 .8 mL) and the mixture stirred at rt for 1 h.
• the aqueous phase was partitioned between 25% NaOH (aq) (200 g) and 2-Me-THF (200 mL), and the organic phase was collected and dried.
• Triethylamine (16.32 mL, 1 17.48 mmol) was added into the organic phase followed by dropwise addition of propionyl chloride (6.0 g, 64.6 mmol) at 0 °C.
• the resulting mixture was stirred at 0 °C for 1 h.
• the reaction mixture was washed with water (1 10 mL) and the resulting organic phase was concentrated in vacuo to give a brown gum.
• Example 67 by heating in acetonitrile/water: 2.0 g of Example 67 (4.440 mol) were dissolved in 10 mL of acetonitrile and 0.5 mL of water at 75°C.
• the invention relates to an administration unit comprising 1- ⁇ (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl ⁇ -propan-1-one citrate, fumarate, napadisylate, phosphate, HCl, hippurate, anhydrous form, or trihydrate.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to PI3K-related diseases including but not limited to autoimmume disorders, intlammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors; conditions, diseases or disorders in which one or more of the functions of B cells such as antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact derma
• PI3K-mediated is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus ery
• haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
• systemic lupus erythematosus polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune intlammatory bowel disease (e.g.
• endocrine opthalmopathy Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; autoimmune disease and of intlammatory conditions, in particular inflammatory
• autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia), acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody- associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idio-pathic sprue
• autoimmune haematological disorders including e.g. hemolytic
• ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
• endocrine ophthalmopathy Graves' disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitis type I), uveitis (anterior, intermediate and posterior as well as panuveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
• idiopathic nephro-tic syndrome or minimal change nephropathy tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dyslipidemia; conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia, Schnitzler syndrome, Waldenstrom's macroglobulinemia, angioedema,
• the invention also relates to administration units comprising combinations of ⁇ drug4 ⁇ with ⁇ drug5 ⁇ , also referred to as ' ⁇ drug4+drug5 ⁇ '.
• Preferred combinations are combinations of any of ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ with any of ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ .
• Preferred combinations are selected from the group consisting of ⁇ drug4a+drug5a ⁇ , ⁇ drug4a+drug5b ⁇ , ⁇ drug4a+drug5c ⁇ , ⁇ drug4a+drug5d ⁇ , ⁇ drug4a+drug5e ⁇ , ⁇ drug4a+drug5t ⁇ , ⁇ drug4a+drug5g ⁇ , ⁇ drug4a+drug5h ⁇ , ⁇ drug4b+drug5a ⁇ , ⁇ drug4b+drug5b ⁇ , ⁇ drug4b+drug5c ⁇ , ⁇ drug4b+drug5d ⁇ , ⁇ drug4b+drug5e ⁇ , ⁇ drug4b+drug5t ⁇ , ⁇ drug4b+drug5g ⁇ , ⁇ drug4b+drug5h ⁇ , ⁇ drug4c+drug5a ⁇ , ⁇ drug4c+drug5b ⁇ , ⁇ drug4c+drug
• aspects (v) of the invention concerns formulations of ⁇ drug6 ⁇ , especially formulations of ⁇ drug6a ⁇ or ⁇ drug6b ⁇ and relates to administration units comprising a solubilized or amorphous form of Nilotinib.
• the invention relates to a form of Nilotinib, namely to solubilized form ( ⁇ drug6a ⁇ ) or amorphous form ( ⁇ drug6b ⁇ ), which is useful for treating chronic myeloid leukemia and gastrointestinal stromal tumors.
• nilotinib ( ⁇ drug6 ⁇ ) refers to 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide of formula I:
• Nilotinib Solubilized or amorphous form of Nilotinib is described in WO2013174082 , which is incorporated by reference.
• WO2013174082 describes: The present invention provides solublized or amorphous pharmaceutical compositions of nilotinib or a pharmaceutically acceptable salt thereof using one or more organic acids that function as a solubilizing agent, increasing the bioavailability of nilotinib and suppressing the food effect associated with certain compositions of nilotinib.
• the pharmaceutical compositions are in the form of oral dosage forms, preferably solid oral dosage forms, including capsules, tablets and multiparticulates.
• a dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof, 3.
• a dosage form of item 2 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid. 4.
• a dosage form of item 2 or 3 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, having a fasted state bioavailability that exceeds 130% of marketed TasignaTMhard-gelatin capsule. 6.
• a dosage form of any one of items 3 to 5 comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, having a fed/fasted ratio of 0.8-1 .5 for AUC and/or Cmax. 7.
• any one of items 3 to 6, wherein said at least one organic acids is selected from acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesufonic acid and ascor
• the dosage form wherein the organic acid is citric acid.
• the dosage form, wherein the organic acid is lactic acid.
• the dosage form, wherein the organic acid is acetic acid.
• the dosage form further comprising a surfactant or an anionic polymer.
• the dosage form, wherein the surfactant or the anionic polymer is CYP3A4 or Pg-P inhibitor.
• the dosage form, wherein the surfactant is Poloxamer 407 and/or Vitamin E TPGS.
• the dosage form, wherein the polymer is Eudragid L100-55.
• the dosage form, wherein the dosage form has water content of less than 10% w/w, preferably less than 5% w/w, particuarly les than 2 % w/w.
• the dosage form further comprising excipients for solidifying the dosage form.
• the dosage form, wherein the dosage form is solid.
• the dosage form, wherein the dosage form is a tablet.
• the dosage form, wherein the dosage form is a capsule.
• a method for preparing a dosage form comprising amorphous 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid, comprising the step of melt extruding 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and the at least one organic acid.
• a method of preparing a dosage form comprising 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and at least one organic acid comprising the step of spray drying at least partly dissolved of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide or a pharmaceutically acceptable salt thereof and adding the at least one organic acid.
• the method wherein the polymer is Eudragid L100-55.
• the methods comprising a further step of obtaining a solid dosage form.
• the method wherein the solid dosage form is a tablet or a capsule.
• Use of organic acid for suppressing the food effect associated with pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof, A dosage form of any one of the above items for use as a medicine.
• the dosage form, wherein the medicine is stored under refrigeration at 2 to 8°C.
• the administration unit accoding to the invention comprisies a solubilized or amorphous form of a salt of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide, preferably a solubilized or amorphous form of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide acetic acid salt, solubilized or amorphous form of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidi-nyl]amino]-N-[5-(4-methyl-1 H-imid
• WO2012174082 discloses the following examples:
• Example 1 Nilotinib Lactic Acid Formulation It was surprisingly found that nilotinib had a very high solubility in lactic acid (> 600 mg/ml at 65°C) and could maintain its solubility at intestinal pH in presence of surfactants and/or polymers.
• Nilotinib solubilized modified release solid dosage forms containing lactic acid were developed. This formulation demonstrated higher bioavailability in both fasted and fed condition compared to FMI, and suppressed the food effect associated with nilotinib.
• Surfactants and/or polymers were used to prevent the precipitation after solubilized nilotinib is released from the formulation matrix.
• this formulation matrix is in the liquid form.
• the formulation could be solidified at room temperature. This improved the physical and chemical stability of nilotinib in the formulation.
• the solid state also provided the opportunity to modulate the drug release rate.
• nilotinib lactic acid formulations are described in the following table: Ingredient (mg/dose) Formulation A Formulation B Nilotinib free base 100 200 Lactic acid 175 350 Poloxamer 407 60 70 Vitamine TPGS 50 60 HPMC 3 cps 100 150 PEG3350 160 - Total 645 830 In these formulations, lactic acid was used to dissolve nilotinib and maintain nilotinib in the liquid/solubilized state. Poloxamer 407 and VitaminE TPGS polymer and/or surfactant, respectively, were used as precipitation inhibitors and in addition these excipients are also known CYP3A4 & Pg-P inhibitors.
• HPMC 3 cps was used as the control release agent.
• PEG3350 was used as a solidifying agent to convert the formulation to a solid state at RT. Manufacturing process : 1. The blend of Poloxamer 407, Vitamin-E TPGS and/or PEG3350 was heated to 65°C to form a clear solution (solution A). 2. AMN107 free base was dissolved in lactic acid at 65°C (solution B). 3. Mix solution A and B, and then add HPMC 3 cps to form a suspension. 4. The molten suspension was filled in Size 0/00 capsules and allowed to solidify at room temperature.
• Nilotinib has demanding purity and stability requirements for a mutagenic impurity 371- 03 ( ⁇ 3 ppm at release and ⁇ 6 ppm during stability).
• Formulation B exhibits impurity levels of 2.3 ppm at the initial time point, but exhibits impurity levels of 19.4 ppm after 1 month storage at RT, which is over the 6 ppm specification limit.
• Magnesium stearate (internal) was added to step 1 and blended (80 revolutions). The blend was roller compacted. The ribbon was milled and screened through No. 18 mesh. The external magnesium stearate was added to the granules from step 4 and blended (80 revolutions). This final blend was then compressed. For capsule, no external magnesium stearate was added before filling into capsules.
• MR tablet B (fast) and MR tablet C (slow) were dry blended as described in the following steps. 1. All the ingredients except magnesium stearate were passed through No.35 mesh and blended (200) revolutions. Magnesium stearate was added to step 1 and blended (80 revolutions). The final blend was compressed into tablets.
• Dissolution Two step dissolution conditions used for the following nilotinib formulations, IR capsule, IR tablet and MR tablet B (fast) are: 37°C; Step 1 , 0-60 minutes 500ml pH 2 buffer, Step 2, > 60 minutes 1000ml pH 6.8 buffer; Paddle at 75rpm.
• Two step dissolution conditions used for MR tablet C (slow) are: 37°C; Step 1 , 0-120 minutes 500ml pH 2 buffer, Step 2, 120-180 minutes 1000ml pH 6.8 buffer; Paddle at 75rpm.
• the dissolution data for IR tablet and capsule and MR tablet B (fast) and MR tablet C (slow) are summarized in Figures 9 and 10.
• MR Tablet B fast containing Eudragit L100-55 shows a slightly slower release rate in pH 2 and higher supersaturation in pH 6.8 compared to IR tablet without Eudragit L100-55.
• Eudragit L100-55 is an anionic polymer soluble at pH 6.8 and provides inhibition of precipitation. Thus the use of other precipitation inhibitors is expected to provide similar supersaturation.
• the slow release MR tablet C formulation was developed through screening of several viscosity grade polymers and subsequent selection of an appropriate polymer. The selected polymer, HPMC K100 LV CR had the required viscosity and provided the expected release profile.
• the MR tablet C (slow) containing Eudragit L100-55 and HPMC K100 LV CR demonstrated a slow release in pH 2.
• Dog PK data 50mg Nilotinib MR (fast & slow) formulations solubilized using citric acid were tested in dogs.
• the solid-Suspeneded MicroEmulsion (SSME) formulation previously tested in the clinic was used as the control since it showed a higher bioavailability and moderate suppression of food effect in the human clinical study compared to FMI and thus was deemed to be a better reference to be compared with.
• Figure 1 of WO2012174082 summarizes the dissolution profile for a nilotinib lactic acid formulation.
• Figure 2 of WO2012174082 summarizes Cmax data for a nilotinib lactic acid formulation tested in dogs.
• Figure 3 of WO2012174082 summarizes AUC data for a nilotinib lactic acid formulation tested in dogs.
• Figure 4 of WO2012174082 summarizes X-ray diffraction (XRD) data for a nilotinib citric acid intermediate.
• Figure 5 of WO2012174082 summarizes differential scanning calorimetric data for a nilotinib citric acid intermediate.
• Figure 6 of WO2012174082 summarizes thermogravimmetric data for a nilotinib citric acid intermediate.
• Figure 7 of WO2012174082 summarizes thermogravimmetric data for a nilotinib citric acid intermediate.
• Figure 8 of WO2012174082 summarizes XRD data for a nilotinib citric acid formulation after 6 month storage at ambient condition.
• Figure 9 of WO2012174082 summarizes the two-step dissolution profile for a nilotinib citric acid formulation.
• Figure 10 of WO2012174082 summarizes the two-step dissolution profile for a nilotinib citric acid MR tablet (slow).
• Figure 1 1 of WO2012174082 summarizes C max data for a nilotinib citric acid formulation tested in dogs.
• Figure 12 of WO2012174082 summarizes AUC data for a nilotinib citric acid formulation tested in dogs.
• solubilized or amorphous form is the solubilized or amorphous form of Nilotinib.
• the invention relates now to an administration unit comprising solubilized or amorphous form.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to chronic myeloid leukemia and gastrointestinal stromal tumors.
• Aspect (vi) of the invention relates to ⁇ drug7 ⁇ , especially formulation ⁇ drug7a ⁇ and relates to administration units comprising X21.
• the invention relates to a administration unit of a pharmaceutical formulation, herein called 'X21', comprising an antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody: a) does not block PCSK9 binding to the LDLR and b) inhibits PCSK9-mediated degradation of LDLR, which is useful for treating diseases.
• 'X21' comprising an antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody: a) does not block PCSK9 binding to the LDLR and b) inhibits PCSK9-mediated degradation of LDLR, which is useful for treating diseases.
• PCSK9 proprotein convertase subtilisin/kexin type 9
• X21 comprising an antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody: a) does not block PCSK9 binding to the LDLR and b) inhibits PCSK9-mediated degradation of LDLR is described in WO2012168491 , which is incorporated by reference.
• PCSK9 proprotein convertase subtilisin/kexin type 9
• X21 provides as a stable, highly concentrated liquid pharmaceutical composition comprising at least about 10 mg/mL of said antibody.
• the invention provides a lyophilized pharmaceutical composition which comprises at least about 10 mg/ml of said antibody after reconstitution in solution.
• the use of a formulation according to invention is provided for administration to an individual having hypercholesterolemia or a high baseline LDL-C level.
• X21 is directed to a dosage form comprising: a liquid or lyophilized pharmaceutical composition comprising: a) least about 10 mg/mL of said antibody and b) at least one pharmaceutically acceptable excipient.
• X21 provides a method of producing a lyophilized pharmaceutical composition comprising at least about 10 mg/mL of said antibody post reconstitution, by contacting a) said antibody with b) at least one pharmaceutically acceptable excipient.
• Another aspect of X21 relates to a method for producing said liquid or lyophilized formulation.
• the invention of this application relates now to an administration unit comprising X21.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to diseases.
• Aspect (vii) of the invention relates to ⁇ drug8 ⁇ , especially ⁇ drug8a ⁇ or ⁇ drug8b ⁇ and relates to administration units comprising the (S)-enantiomer or (R)-enantiomer of N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide.
• the invention relates to heterocyclic sulfonamide compounds and pharmaceutical compositions thereof, in particular heterocyclic sulfonamide compounds that are specific inhibitors of kinase activity of MEK.
• the invention also relates to the use of the compounds and compositions thereof in the management of hyperproliferative diseases like cancer and inflammation.
• the invention provides the compounds (S)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide and (R)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide:
• N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide refers to (S)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide or (R)-N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide, and salts thereof.
• the compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
• solvates are considered pharmaceutical compositions, e.g., a compound of the present invention in combination with an excipient, wherein the excipient is a solvent.
• the compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
• the invention relates to a method for treating a disease or condition related to the hyperactivity of MEK, or a disease or condition modulated by the MEK cascade, comprising administration of an effective therapeutic amount of a compound of the present invention.
• the invention relates to a method for treating proliferative diseases, such as cancer, comprising administration of an effective amount of a compound of the present invention.
• cancers include but are not limited to: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, lymphoma, chondromatous hanlartoma, inesothelioma, esophageal squamous cell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma, stomach and small bowel carcinoid tumors, adenocarcinoma, Karposi's sarcoma, leiomyoma, heman
• the invention includes a method of treating cancer selected from non-small cell lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, breast cancer, prostate cancer, thyroid cancer, melanoma, adenomas and carcinomas of the ovary, eye, liver, biliary tract, and nervous system and advanced solid tumors with KRAS, NRAS and BRAF mutations, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.
• the compounds of the invention may also be useful in the treatment of other diseases or conditions related to the hyperactivity of MEK.
• the invention relates to a method of treatment of a disorder selected from: xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiomegaly; stroke (such as acute focal ischemic stroke and global cerebral ischemia); heart failure; septic shock; asthma; chronic obstructive pulmonary disorder; Alzheimer's disease; and chronic or neuropathic pain.
• a disorder selected from: xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiomegaly; stroke (such as acute focal ischemic stroke and global cerebral ischemia); heart
• Compounds of the present invention may also be useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV) human papilloma virus (HPV), cytomegalovirus (CMV], and Epstein-Barr virus (EBV).
• HIV hepatitis
• HBV hepatitis virus
• HPV human papilloma virus
• CMV cytomegalovirus
• EBV Epstein-Barr virus
• Compounds of the present invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune disease, atherosclerosis and inflammatory bowel diseases, e.g. Crohn's disease and ulcerative colitis.
• the invention relates to a solid form of N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide, namely to (S)-enantiomer or (R)-enantiomer of N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)-cyclopropane-1-sulfonamide, which is useful for treating diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
• a compound of formula 4a can be prepared by reacting a compound of formula 2 with a compound of formula 3 a in the presence of a suitable amine (for example, triethylamine, N,N-diisopropylethylamine, triisopropylamine, or the like), a suitable catalyst (for example, N,N-dimethylpyridin-4-amine, or the like) and a suitable solvent (for example, DCM, 1,2-dichloromethane, toluene, tetrahydrofuranyl, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 12 hours to complete.
• a suitable amine for example, triethylamine, N,N-diisopropylethylamine, triisopropylamine, or the like
• a suitable catalyst for example, N,N-dimethylpyridin-4-amine, or the like
• a suitable solvent for example, DCM, 1,2-dichloromethan
• a compound of formula 5a can be prepared from a compound of formula 4a in the presence of a suitable base (for example, potassium trimethylsilanoate, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 12 hours to complete.
• the S-enantiomer can be prepared from a compound of formula 5a in the presence of a suitable Lewis acid (for example, trichlorborane, boron trifluoride, boron tribromide, or the like) and a suitable solvent (for example, dichloromethane, 1,2-dichloromethane, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 1 hour to complete.
• a suitable Lewis acid for example, trichlorborane, boron trifluoride, boron tribromide, or the like
• a suitable solvent for example, dichloromethane, 1,2-dichloromethane, or the like.
• a compound of formula 4b can be prepared by reacting a compound of formula 2 with a compound of formula 3b in the presence of a suitable amine (for example, triethylamine, N,Ndiisopropylethylamine, triisopropylamine or the like), a suitable catalyst (for example, N,N-dimethylpyridin-4-amine or the like) and a suitable solvent (for example, DCM, 1,2-dichloromethane, toluene, tetrahydrofuran, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 12 hours to complete.
• a suitable amine for example, triethylamine, N,Ndiisopropylethylamine, triisopropylamine or the like
• a suitable catalyst for example, N,N-dimethylpyridin-4-amine or the like
• a suitable solvent for example, DCM, 1,2-dichloromethane, toluene,
• a compound of formula 5b can be prepared from a compound of formula 4b in the presence of a suitable base (for example, potassimn trimethylsilanoate, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 12 hours to complete.
• the R-enantiomer can be prepared from a compound of formula 5b in the presence of a suitable Lewis acid (for example, trichlorborane boron trifluoride, boron tribromide, or the like) and a suitable solvent (for example, dichloromethane, 1,2-dichloromethane, or the like). The reaction proceeds at a temperature of about 25°C and can take up to about 1 hour to complete.
• the invention relates to an administration unit comprising (S)-enantiomer or (R)-enantiomer of N-(4,5-difluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-7-yl)-1-(2,3-dihydroxypropyl)-cyclopropane-1-sufonamide.
• the administration unit according to the invention is useful for treating various diseases and disorders which include but are not limited to diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
• WO2012/168884 discloses the following examples: Pharmacological data : The inhibitory properties of compounds of present invention may be demonstrated using any one of the following test procedures: A BRAF-MEK-ERK cascade assay is used to evaluate the effects of these compounds as inhibitors of the MAP kinase pathway. An enzymatic cascade assay is set up using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557), human full length MEK1 kinase (Cat No. 14-706) and human full length active MAP Kinase 2/ERK2 (Cat No. 14-536) enzymes procured from Upstate. TR-FRET (Time resolved fluorescence resonance energy transfer) detection technology is used for the read out.
• V599E human activated BRAF
• MEK1 kinase Cat No. 14-706
• TR-FRET Time resolved fluorescence resonance energy transfer
• the assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01 % Tween 20, 0.1 nM activated BRAF, 3 nM inactive MEKI,IO nM inactive ERK2, 100 ⁇ M ATP and 500 nM long chain biotin-peptide substrate (LCB- FFKNIVTPRTPPP) in a 384 well format.
• the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu-labeled phospho-serine/threonine antibody (Cat. No.ADO1 76-Perkin Elmer), 20 nM SA-APC (Cat No.
• the TR-FRET signal (Excitation at 340 nm, Emission at 615 nm and 665 nm) is read with 50 ⁇ 8 delay time on a Victor3 V fluorimeter. The data is calcuated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes. Each individual IC50 is determined using a 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).
• An in-vitro MAP kinase assay is set up using activated MAP kinase 2/ERK2 (Cat. No.14-550) obtained from Upstate. TR-FRET detection technology is used for the read out.
• the assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 0.01 % Tween 20, 1 nM activated ERK2, 100 ⁇ M ATP and 500 nM long chain biotin-peptide substrate (LCB- FFKNIVTPRTPPP) in a 384 well format.
• the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu-labeled phospho-serine/threonine antibody (Cat.No. ADO 176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100-Perkin Elmer) is added.
• the TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with 50 ⁇ 8 delay time on Victor3 V fluorimeter. The data is calcuated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes. The radioactive filter binding assay is standardized using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557) and kinase dead MEK1 (K97R) (Cat No. 14-737) procured from Upstate.
• V599E human activated BRAF
• K97R kinase dead MEK1
• the dried P81 filter papers are read in a Micro-beta Trilux scintillation counter.
• the final concentration of DMSO is 1 % in the assay.
• Compounds are screened at 10 ⁇ M concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
• XTT is a yellow tetrazolium salt that is cleaved to an orange formazan dye by the mitochondria of metabolically active cells.
• the procedure allows for rapid determination in a microtitre plate, to give reproducible and sensitive results.
• A375 cells are grown in DMEM media containing 10% FBS and ImM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells/well. After allowing the cells to adhere overnight, compound is added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001, and 0.0001 ⁇ M. The assay is set up in triplicates for each concentration. DMSO concentrations are kept at 0.5% /well.
• the XTT assay is performed. Wells are washed once with PBS. 100 ⁇ of DMEM media without phenol red or FBS is added to each well. A working solution of XTT containing lmg/ml XTT and 100 ⁇ of PMS (stock concentration 0.383 mg/ml) per 5ml is prepared. 50 ⁇ of the working solution of XTT is added to each well. Absorbance of the plate is read at 465nm using a Spectramax 190 (Molecular Devices). The absorbance from wells with media and XTT alone, but without cells is considered the blank and subtracted from readings from all wells. The cell viability assay is further described in Scudiero, et.
• Percentage viability is calcuated considering the blank subtracted value from wells treated with DMSO alone as 100% viable.
• GI5 0 values are calculated using Graphpad Prism, using non-linear regression curve fit for sigmoidal dose response (variable slope). Compounds of the invention were evaluated in this cell viability assay.
• Example 1A has a GI5 0 of 13.4 nM and Example IB has a GI 50 of 29.6 nM, while Example 1 has a GI5 0 of 17.6 nM.
• A375 P-Erk Human melanoma A375 cells were seeded at 50,000 cells per well in 100 ⁇ growth medium in Costar 96 well black clear bottom plates and placed at 37° C/5% CO 2 over night. Test compounds were diluted in DMSO to generate a concentration curve. A 5 mM stock was used for the highest concentration at 500 times; to yield a final concentration of 10 ⁇ M with 3-fold dilutions down to 0.000 I ⁇ M.
• Example 1A The EC50 of Example 1A is 6.4 nM compared with 15.6nM for Example IB and 12.2nM for Example 1.
• Pharmacokinetics athvmic nude rats For pharmacokinetics studies, the following parameters were calcuated by non-compartmental regression analysis using Winnonlin 5.0 software (Pharsight, Mountain View, CA, USA): half life in plasma (t ⁇ t e rm); plasma clearance (CL); plasma maximum concentration (Cmax); plasma area-under-the-concentration- time-curve (AUC); and percent oral bioavailability (F%). Pharmacokinetics parameters in rat for some compounds of the invention are given in the table below: i.v. (0.5 mg/kg) p.o.
• Examples 1A and IB show improved PK-parameters compared to Example 1 (one-way analysis of variance).
• A375 B-RafV 600E human melanoma model in rat - PK-PD experiment A375 cells were thawed using a 37°C water bath. Cells were transferred to a tube containing 1Omls of warm DMEM medium. The tube was centrifuged for 5 minutes at 1200 rpm and the supernatant was discarded. The cell pellet was re-suspended and transferred to a 75 cm 2 tissue culture flask containing 15mls of medium and cultured at 37°C in a 5% CO 2 incubator. On the day of the cells implantation, cells were harvested (about 85% confluent), and re-suspended in cold medium containing 4 mg/ml of matrigel.
• This cell suspension was injected, subcutaneously, to athymic-nude pre-irradiated (500 rads) rats.
• Ten million cells (injection volume, 200 ⁇ ) were injected, subcutaneously, into the right flank region of the rats 24 hours after irradiation.
• Tumor bearing rats were randomized when the tumor volume reached approximately 500 mm 3 after about 15 to 20 days. Three rats were used for each time point. Rats were treated orally with a single dose of 10, 30 and 60 mg/kg p.o. of Example 1A and 30 mg/kg of Example IB. Plasma and tumor samples were taken at 4, 12, 24 and 36 hours, post dosing.
• the mRNA expression levels of two direct target genes of MEK substrate P-Erk (DUSP6 and SPRY4) and an indirect target (BMF) can be measured.
• these genes Upon treatment with MEK inhibitors, these genes have been shown to be regulated in a dose-dependent manner in tumor cell lines grown in vitro and in vivo.
• the tumor samples were pulverized, extracted and studied for expression of the transcription factor DUSP6 using a real time quantitative PCR.
• the administration unit according to the invention comprises a therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, wherein at least 10 % by weight of said therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, are present as (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (iii)
• not more than 90 % by weight of said therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, are amorphous.
• Suitable methods include but are not limited to thermal analysis, HPLC and XRPD (see e.g. K.D. Harris, Powder diffraction crystallography of molecular solids, Top Curr Chem., 2012, 315:133-77 ).
• not more than 90 % by weight of said therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, are forms or polymorphs of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, other than (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (iii)
• Suitable methods include but are not limited to thermal analysis, HPLC and XRPD (see e.g. N. Chieng, T. Rades, J.Aaltonen, An overview of recent studies on the analysis of pharmaceutical polymorphs, J Pharm Biomed Anal. 2011, 35:55(4):618-44 ; R. Hilfiker, Polymorphism, Wiley-VCH, 1st ed. 2006 ; H.G. Brittain, Polymorphism in Pharmaceutical Solids (Drugs and the Pharmaceutical Sciences), Informa Healthcare, 2nd ed. 2009 ).
• the therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 0.1 ⁇ g to 2 g of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the therapeutically effective amount of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 1 ⁇ g to 2.5 ⁇ g of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or 2.5 ⁇ g to 5 ⁇ g of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug
• the administration unit according to the invention comprises 0.1 ⁇ g to 2 g of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or
• it comprises 1 ⁇ g to 2.5 ⁇ g of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1e ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (vi)
• ⁇ drug4 ⁇ (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, i.e. preferably contains neither non-crystalline forms of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug3+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, nor crystalline forms other than (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ ,
• the administration unit according to the invention and its constituents i.e. (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, and (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1e ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv)
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1e ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (i) ⁇ d
• a particle size distribution (preferably by volume) such that at least 90 % of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1e ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (i) ⁇ d
• a particle size distribution (preferably by volume) such that at least 50 % of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (vi) ⁇ d
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (vi) ⁇ d
• the administration unit according to the invention contains (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (vi) ⁇ d
• the indicated particle size properties are determined by laser-diffraction method, in particular low angle laser light scattering, i.e. Fraunhofer diffraction.
• the particle size properties can be also determined by microscopy (e.g. electron microscopy or scanning electron microscopy).
• the powder fineness is preferably determined in accordance with USP35 ⁇ 811>. The results of the particle size distribution determined by different techniques can be correlated with one another.
• the administration unit according to the invention is solid, semisolid or liquid.
• the administration unit according to the invention is for administration once daily, or twice daily, or thrice daily, or four times daily, or five times daily, or six times daily.
• the administration unit according to the invention is monolithic or multiparticulate.
• Excipient composition and homogeneity can be determined by standard analysis known to the skilled artisan. Suitable methods include but are not limited to near-infrared chemical imaging.
• the administration unit according to the invention provides controlled release of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention comprises a controlled release matrix or a controlled release coating.
• the administration unit according to the invention has released after 1 hour not more than 90 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 1 hour not more than 80 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 70 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 60 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug8 ⁇
• the administration unit according to the invention has released after 2 hours not more than 90 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 2 hours not more than 80 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 70 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 60 % of (i) ⁇ drug 1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug ⁇
• the administration unit according to the invention has released after 4 hours not more than 90 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 4 hours not more than 80 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 70 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 60 % of (i) ⁇ drug 1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug ⁇
• the administration unit according to the invention has released after 8 hours not more than 90 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 8 hours not more than 80 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 70 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or not more than 60 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug8 ⁇
• the administration unit according to the invention provides immediate release of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 0.5 hours at least 10 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention has released after 0.5 hours at least 20 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or at least 30 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, or at least 40 % of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , or
• the administration unit according to the invention has a total weight of 10 mg to 3 g.
• the administration unit according to the invention has a total weight of 10 to 25 mg, or 25 mg to 50 mg, or 50 mg to 100 mg, or 100 mg to 250 mg, or 250 mg to 500 mg, or 500 mg to 1000 mg, or 1000 mg to 2500 mg.
• the administration unit according to the invention is for systemic or topical administration.
• the administration unit according to the invention is for parenteral administration.
• the administration unit according to the invention is for oral, buccal, opthalmic, nasal, rectal, transmucosal, or intestinal administration. Preferably, it is for oral administration.
• the administration unit according to the invention is selected from the group consisting of tablets, capsules, effervescent tablets, orodispersible tablets, dragees, sachets, drops, suspensions, and powders.
• it is a tablet.
• the administration unit according to the invention is round or oblong; and/or is planar or biconvex.
• the administration unit according to the invention has a round cross-section with a diameter of 1 mm to 20 mm.
• the diameter of the round cross-section is 1 mm to 3 mm, or 3 mm to 5 mm, or 5 mm to 8 mm, or 8 mm to 10 mm, or 10 mm to 13 mm, or 13 mm to 15 mm, or 15 mm to 18 mm, or 18 mm to 20 mm.
• the administration unit according to the invention is oblong and has an aspect ratio of at least 1.1:1.
• the aspect ratio is at least 4:3, or at least 31/3:1, or at least 3:3, or at least 16:10, or at least Psi:1, or at least 5:3, or at least 16:9.
• the administration unit according to the invention has been manufactured by direct compression.
• the administration unit according to the invention has been manufactured by granulation and subsequent compression of granules.
• granulation is wet granulation or dry granulation.
• the administration unit according to the invention has been compacted at a pressure of 10 MPa to 10,000 MPa.
• the administration unit according to the invention has been compacted at a pressure of 10 MPa to 25 MPa, or 25 MPa to 50 MPa, or 50 MPa to 100 MPa, or 100 MPa to 250 MPa, or 250 MPa to 500 MPa, or 500 MPa to 1000 MPa, or 1000 MPa to 2500 MPa, or 2500 MPa to 5000 MPa, or 5000 MPa to 10,000 MPa.
• the administration unit according to the invention comprises a film coating.
• the film coating is enteric.
• Suitable enteric coating materials are known to the skilled artisan and include but are not limited to methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, sodium alginate and stearic acid.
• the film coating comprises a cellulose ether (e.g. hydroxypropylmethyl cellulose) or a synthetic polymer (e.g. polyvinyl alcohol).
• a cellulose ether e.g. hydroxypropylmethyl cellulose
• a synthetic polymer e.g. polyvinyl alcohol
• the film coating has an average thickness of 0.01 ⁇ m to 0.03 ⁇ m, or 0.03 to 0.05 ⁇ m, or 0.05 to 0.1 ⁇ m, or 0.1 to 0.25 ⁇ m, or 0.25 to 0.5 ⁇ m, or 0.5 to 1.0 ⁇ m, or 1.0 ⁇ m to 2.5 ⁇ m, or 2.5 ⁇ m to 5.0 ⁇ m, or 5.0 ⁇ m to 10 ⁇ m, or 10 ⁇ m to 25 ⁇ m, or 25 ⁇ m to 50 ⁇ m, or 50 ⁇ m to 100 ⁇ m, or 100 ⁇ m to 250 ⁇ m, or 250 ⁇ m to 500 ⁇ m, or 500 ⁇ m to 1000 ⁇ m.
• the administration unit according to the invention has a tablet porosity of not more than 90 %.
• it has a tablet porosity of not more than 80 %, or not more than 70 %, or not more than 60 %, or not more than 50 %, or not more than 40 %, or not more than 30 %, or not more than 20 %, or not more than 10 %.
• it has a tablet porosity of not more than 5 %, or not more than 4 %, or not more than 3 %, or not more than 3 %, or not more than 1 %, or not more than 0.5 %, or not more than 0.2 %, or not more than 0.1 %.
• the most common strength test in pharmaceutical applications is the diametral compression test, which is used to calculate the radial tensile strength of a tablet ( Fell, J.T., Newton, J.M., 1970. Determination of tablet strength by diametral compression test. J. Pharm. Sci. 59, 688-691 ).
• the stress conditions have to be such that the tablet fails in tension.
• the fracture occurs through a predetermined diametral cross section of the tablet. Therefore, the radial tensile strength is likely to reflect the average strength of tablet rather than the strength of the weakest plane in the tablet.
• the administration unit according to the invention has a radial tensile strength of 0.1 to 100 MPa.
• it has a radial tensile strength of 0.1 MPa to 0.3 MPa, or 0.3 MPa to 0.5 MPa, or 0.5 MPa to 1.0 MPa, or 1.0 MPa to 2.5 MPa, or 2.5 MPa to 5.0 MPa, or 5.0 MPa to 10 MPa, or 10 MPa to 25 MPa, or 25 MPa to 50 MPa, or 50 MPa to 100 MPa.
• Another method for determining mechanical strength is to measure the axial tensile strength.
• the force necessary to break the tablet is obtained by pulling the tablet parallel to the applied force during the formation of the tablet and this force is then used to calculate the axial tensile strength ( Nyström, C., Malmqvist, K., Mazur, J., Alex, W., Hölzer, A.W., 1978. Measurement of axial and radial tensile strength of tablets and their relation to capping. Acta Pharm. Suec. 15, 226-232 ).
• the fracture will occur through the weakest plane in the tablet. Consequently, this method allows detection of capping tendencies in a tablet.
• the administration unit according to the invention has an axial tensile strength of 0.1 to 100 MPa.
• it has an axial tensile strength of 0.1 MPa to 0.3 MPa, or 0.3 MPa to 0.5 MPa, or 0.5 MPa to 1.0 MPa, or 1.0 MPa to 2.5 MPa, or 2.5 MPa to 5.0 MPa, or 5.0 MPa to 10 MPa, or 10 MPa to 25 MPa, or 25 MPa to 50 MPa, or 50 MPa to 100 MPa.
• the administration unit according to the invention has an average pore size of 0.001 ⁇ m to 1000 ⁇ m.
• it has an average pore size of 0.001 ⁇ m to 0.003 ⁇ m, or 0,003 ⁇ m to 0.005 ⁇ m, or 0.005 ⁇ m to 0.01 ⁇ m, or 0.01 ⁇ m to 0.025 ⁇ m, or 0.025 ⁇ m to 0.05 ⁇ m, or 0.05 ⁇ m to 0.1 ⁇ m, or 0.1 ⁇ m to 0.25 ⁇ m, or 0.25 ⁇ m to 0.5 ⁇ m, or 0.5 ⁇ m to 1 ⁇ m, or 1 ⁇ m to 2.5 ⁇ m, or 2.5 ⁇ m to 5 ⁇ m, or 5 ⁇ m to 10 ⁇ m, or 10 ⁇ m to 25 ⁇ m, or 25 ⁇ m to 50 ⁇ m, or 50 ⁇ m to 100 ⁇ m, or 100 ⁇ m to 250 ⁇ m, or 250 ⁇ m to 500 ⁇ m, or
• the pore size distribution of a tablet may be assessed by methods that are known to the skilled artisan and include but are not limited to gas adsorption (e.g. Stanley-Wood, N.G., Johansson, M.E., 1980. Variation of intra- and inter-particle porosity with degree of compaction. Analyst 105, 1104-1112 ; Westermarck, S., Juppo, A.M., Kervinen, L., Yliruusi, J., 1998. Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption. Eur. J. Pharm. Biopharm.
• mercury porosimetry e.g. Stanley-Wood, N.G., Johansson, M.E., 1980. Variation of intra- and inter-particle porosity with degree of compaction. Analyst 105, 1104-1112 ; Juppo, A.M., 1996. Relationship between breaking force and pore structure of lactose, glucose and mannitol tablets. Int. J. Pharm.127, 95-102 ; Westermarck, S., Juppo, A.M., Kervinen, L., Yliruusi, J., 1998.
• Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption. Eur. J. Pharm. Biopharm. 46, 61-86 ). These techniques are complementary, in that mercury porosimetry can be used to measure larger pores (the lower size limit is about 0.003 ⁇ m in diameter) while gas adsorption allows measurement of smaller pores. For further details it is also referred to S. Lowell et al., Characterization of Porous Solids and Powders: Surface Area, Pore Size and Density (Particle Technology Series), Springer, 2010 .
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not more than 0.1 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not more than 0.1 ⁇ m.
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not less than 0.1 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not less than 0.1 ⁇ m.
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not more than 1 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not more than 1 ⁇ m.
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not less than 1 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not less than 1 ⁇ m.
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not more than 10 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not more than 10 ⁇ m.
• the administration unit according to the invention has a pore size distribution such that at least 10 % of the pores have a pore size of not less than 10 ⁇ m.
• the pore size distribution is such that at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the pores have a pore size of not less than 10 ⁇ m.
• the administration unit according to the invention has a water content of not more than 5 % by weight, relative to the total weight of the tablet.
• it has a water content of not more than 4 % by weight, or not more than 3 % by weight, or not more than 2 % by weight, or not more than 1 % by weight, or not more than 0.5 % by weight, or not more than 0.1 % by weight, relative to the total weight of the tablet.
• the administration unit according to the invention has a true density of 0.60 to 1.40 g cm-3.
• it has a true density of 0.60 to 0.65 g cm-3, or 0.65 to 0.70 g cm-3, or 0.70 to 0.75 g cm-3, or 0.75 to 0.80 g cm-3, or 0.80 to 0.85 g cm-3, or 0.85 to 0.90 g cm-3, or 0.90 to 0.95 g cm-3, or 0.95 to 1.00 g cm-3, or 1.00 to 1.05 g cm-3, or 1.05 to 1.10 g cm-3, or 1.10 to 1.15 g cm-3, or 1.15 to 1.20 g cm-3, or 1.20 to 1.25 g cm-3, or 1.25 to 1.30 g cm-3, or 1.30 to 1.35 g cm-3, or 1.35 to 1.40 g cm-3.
• the administration unit according to the invention has an apparent density of 0.60 to 1.40 g cm-3.
• it has an apparent density of 0.60 to 0.65 g cm-3, or 0.65 to 0.70 g cm-3, or 0.70 to 0.75 g cm-3, or 0.75 to 0.80 g cm-3, or 0.80 to 0.85 g cm-3, or 0.85 to 0.90 g cm-3, or 0.90 to 0.95 g cm-3, or 0.95 to 1.00 g cm-3, or 1.00 to 1.05 g cm-3, or 1.05 to 1.10 g cm-3, or 1.10 to 1.15 g cm-3, or 1.15 to 1.20 g cm-3, or 1.20 to 1.25 g cm-3, or 1.25 to 1.30 g cm-3, or 1.30 to 1.35 g cm-3, or 1.35 to 1.40 g cm-3.
• the administration unit disintegrates within 6000 seconds. Preferably, it disintegrates within 5500 seconds, or within 5000 seconds, or within 4500 seconds, or within 4000 seconds, or within 3500 seconds, or within 3000 seconds, or within 2500 seconds, or within 2000 seconds, or within 1500 seconds, or within 1000 seconds, or within 750 seconds, or within 500 seconds, or within 250 seconds.
• the administration unit according to the invention is a capsule.
• it comprises a multitude of particulates comprising (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (iv) ⁇ drug
• it comprises at least 2 particulates, or at least 3 particulates, or at least 4 particulates, or at least 5 particulates, or at least 6 particulates, or at least 7 particulates, or at least 8 particulates, or at least 9 particulates, or at least 10 particulates.
• the capsule material comprises hard gelatine.
• the administration unit according to the invention comprises at least 2 different types of particulates that differ from each other in at least one property selected from the group consisting of nature of excipients, content of excipients, content of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5e ⁇ ,
• the administration unit according to the invention passes the storage stability test according to Ph. Eur. under accelerated storage conditions at 40°C and 75 % rel. humidity.
• it has a storage stability for at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months according to Ph. Eur. under accelerated storage conditions at 40°C and 75 % rel. humidity.
• the administration unit provides the peak plasma level within 0.1 hour to 36 hours after administration.
• it provides the peak plasma level within 0.1 hour to 1 hour, or 1 hour to 2 hours, or 2 hours to 3 hours, or 3 hours to 4 hours, or 4 hours to 5 hours, or 5 hours to 6 hours, or 6 hours to 7 hours, or 7 hours to 8 hours, or 8 hours to 9 hours, or 9 hours to 10 hours, or 10 hours to 11 hours, or 11 hours to 12 hours, or 12 hours to 13 hours, or 13 hours to 14 hours, or 14 hours to 15 hours, or 15 hours to 16 hours, or 16 hours to 17 hours, or 17 hours to 18 hours, or 18 hours to 19 hours, or 19 hours to 20 hours, or 20 hours to 21 hours, or 21 hours to 22 hours, or 22 hours to 23 hours, or 23 hours to 24 hours, after administration.
• the administration unit according to the invention comprises one or more excipients independently selected from the group consisting of antiadherents, binders, disintegrants, fillers, diluents, flavors, colors, lubricants, glidants, sorbents, surfactants, preservatives and sweeteners.
• excipients independently selected from the group consisting of antiadherents, binders, disintegrants, fillers, diluents, flavors, colors, lubricants, glidants, sorbents, surfactants, preservatives and sweeteners.
• the antiadherent is selected from the group consisting of silicon dioxide, talc, talc waxes, stearates (e.g. magnesium, calcium and sodium), stearic acid, stearowet, boric acid, sodium chloride, DL-leucine, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, and magnesium lauryl sulfate.
• stearates e.g. magnesium, calcium and sodium
• stearic acid stearowet
• boric acid sodium chloride
• DL-leucine sodium oleate
• sodium benzoate sodium acetate
• sodium lauryl sulfate sodium lauryl sulfate
• magnesium lauryl sulfate magnesium lauryl sulfate.
• Magnesium stearate is particularly preferred.
• the binder is selected from the group consisting of saccharides and their derivatives; proteins; gums; silicates; and synthetic polymers.
• the binder is a saccharide or a derivative thereof selected from the group consisting of disaccharides (e.g. sucrose, glucose or lactose); polysaccharides and their derivatives (e.g. starch, pregelatinized starch, cellulose, microcrystalline cellulose, polysaccharide acids, cellulose ethers [e.g.
• alginic acid and salts thereof e.g. sodium alginate
• sugar alcohols e.g. xylitol, sorbitol or maltitol
• the binder is a protein selected from gelatin; or wherein the binder is a gum (e.g. acacia gum, guar gum, or tragacanth gum); or wherein the binder is a silicate (e.g.
• binder is a synthetic polymer selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer, polymethacrylate polymer, polyvinylalcohol, and polyethylene glycol.
• the disintegrant is selected from the group consisting of cross-linked polymers (e.g. cross-linked polyvinylpyrrolidone [crospovidone] or cross-linked sodium carboxymethyl cellulose [croscarmellose sodium]), starches (e.g. corn or potato), pregelatinized starch, modified starch (e.g. sodium starch glycolate), algenic acid, alginates (e.g. sodium alginate), carboxymethylcellulose, microcrystalline cellulose, clays (e.g. magnesium aluminum silicate), and gums (e.g. agar, guar, locust bean, karaya, pectin, or tragacanth gum).
• cross-linked polymers e.g. cross-linked polyvinylpyrrolidone [crospovidone] or cross-linked sodium carboxymethyl cellulose [croscarmellose sodium]
• starches e.g. corn or potato
• pregelatinized starch e.g. sodium starch glycolate
• algenic acid e
• the filler is selected from the group consisting of plant cellulose, microcrystalline cellulose, inorganic phosphates (e.g. dibasic calcium phosphate or tricalcium phosphate), inorganic carbonates such as calcium carbonate, inorganic sulfates such as calcium sulfate dihydrate, sugars and sugar alcohols (e.g. lactose, glucose, inositol, mannitol, sorbitol, sucrose, dextrose, maltodextrins, and fructose), magnesium stearate, calcium lactate trihydrate, starch (e.g. corn, wheat, maize, potato or rice starch), and modified starch (e.g. carboxymethyl starch).
• inorganic phosphates e.g. dibasic calcium phosphate or tricalcium phosphate
• inorganic carbonates such as calcium carbonate
• inorganic sulfates such as calcium sulfate dihydrate
• sugars and sugar alcohols e.
• the lubricant is hydrophilic or hydrophobic.
• the lubricant is selected from the group consisting of talc, silica, stearin, fatty acids (e.g. stearic acid) or fatty acid derivatives, metal stearates (e.g. magnesium stearate, calcium stearate, or zinc stearate), glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, polyalkylene glycols (e.g. polyethylene glycol), starch, light mineral oil, sodium benzoate, and sodium chloride.
• fatty acids e.g. stearic acid
• metal stearates e.g. magnesium stearate, calcium stearate, or zinc stearate
• glyceryl monostearate e.g. magnesium
• the glidant is selected from the group consisting of fumed silica, cornstarch, talc, and magnesium carbonate.
• the surfactant is selected from the group consisting of sodium lauryl sulfate, polyethylene-polypropylene glycol co-polymers, poly(oxyethylene)-poly(oxypropylene)-block-copolymers (e.g. poloxamers).
• the preservative is selected from the group consisting of antioxidants (e.g. vitamin A, vitamin C, vitamin E, retinyl palmitate, selenium, ascorbyl palmitate, sodium ascorbate), amino acids (e.g. cysteine or methionine), citric acid and its salts (e.g. sodium citrate), synthetic preservatives (e.g.
• parabens such as methyl paraben or propyl paraben; butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, propyl gallate), hypophosphorous acid, sodium bisulfite, sodium formaldehyde sulfoxylate, and sodium metabisulfite.
• the administration unit according to the invention passes the friability test according to Ph. Eur.
• the weight loss in the friability test according to Ph. Eur. is not more than 2.0 % by weight, or not more than 1.5 % by weight, or not more than 1.0 % by weight, or not more than 0.5 % by weight, or not more than 0.4 % by weight, or not more than 0.3 % by weight, or not more than 0.2 % by weight, or not more than 0.1 % by weight.
• the administration unit according to the invention passes the test uniformity of content of single-dose preparations according to Ph. Eur.
• the administration unit according to the invention does not comprise any active pharmaceutical ingredient other than (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention is for storage not above 50 °C. Preferably, it is for storage not above 25 °C.
• the administration unit according to the invention is not identical with any of the administration units that are individualized in the experimental section of (i) WO2013010916 , (ii) WO2013006532 , (iii) WO2013001445 , (iv) WO2013001445 , (v) WO2012174082 , (vi) WO2012168491 , and (vii) WO2012168884 , respectively, which are incorporated by reference.
• the invention also relates to the administration unit according to the invention for use in the treatment of a disorder or a disease in a mammal.
• the mammal is a human.
• the mammal is an adult.
• the mammal does not suffer from liver damage and/or kidney damage.
• the mammal is not pregnant.
• the mammal is not allergic against (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the administration unit according to the invention is administered orally with a liquid.
• the liquid is water, milk, juice or lemonade.
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, is 0.0001 mg/kg body weight to 100 mg/kg body weight.
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 0.0001 mg/kg body weight to 0.0003 mg/kg body weight, or 0.0003 mg/kg body weight to 0.0005 mg/kg body weight, or 0.0005 mg/kg body weight to 0.001 mg/kg body weight, or 0.001 mg/kg body weight to 0.0025 mg/kg body weight, or 0.0025 mg/kg body weight to 0.005 mg/kg body weight, or 0.005 mg/kg body weight to 0.01 mg/kg body weight, or 0.01 mg/kg body weight to 0.025 mg/kg body weight, or 0.025 mg/kg body weight to 0.05 mg/kg body weight, or 0.05 mg/kg body weight to 0.1 mg/kg body weight
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, is 0.001 mg to 5000 mg.
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 0.001 mg to 0.003 mg, or 0.003 mg to 0.005 mg, or 0.005 mg to 0.01 mg, or 0.01 mg to 0.025 mg, or 0.025 mg to 0.05 mg, or 0.05 mg to 0.1 mg, or 0.1 mg to 0.25 mg, or 0.25 mg to 0.5 mg, or 0.5 mg to 1 mg, or 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 10 mg, or 10 mg to 25 mg, or 25 mg to 50 mg, or 50 mg to 100 mg, or 100 mg to 250 mg, or 250 mg to 500 mg, or 500 mg to 1000 mg, or 1000 mg to 1250 mg, or 1250 mg to 1500 mg
• the invention also relates to a packaging comprising one or more administration units according to the invention.
• the packaging according to the invention comprises a material selected from the group consisting of paper, cardboard, paperboard, metal foil and plastic foil.
• the packaging according to the invention is a blister packaging.
• a preferred blister packaging includes but is not limited to PVC-blister, PVDC-blister, PVC/PVDC-blister, moisture-proof packaging material such as aluminium foil blister pack, alu/alu blister, transparent or opaque polymer blister with pouch.
• An alternative packaging according to the invention is a polypropylene tube, glass bottle and HDPE bottle optionally containing a child-resistant feature.
• the primary packaging material may comprise a desiccant such as molecular sieve or silica gel to improve chemical stability of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• a desiccant such as molecular sieve or silica gel to improve chemical stability of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• Opaque packaging such as colored blister materials, tubes, brown glass bottles or the like can be used to prolong shelflife of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, by reduction of photodegradation.
• the packaging according to the invention comprises a multitude of at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10 administration units according to the invention.
• the administration units do not substantially differ in at least one property selected from the group consisting of nature of excipients, content of excipients, content of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f); (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4
• the administration units differ in said at least one property by not more than 5 %, or not more than 4 %, or not more than 3 %, or not more than 2 %, or not more than 1 %, or not more than 0.5 %, or not more than 0.1 %.
• all administration units are substantially identical.
• the invention also relates to the packaging according to the invention for use in the treatment of a disorder or a disease, wherein one or more administration units of said multitude are administered on a first day, and one or more administration units of said multitude are administered on a second day following said first day.
• one or more administration units of said multitude are administered on one or more subsequent days following said second day.
• the time interval between the administration of an administration unit and the administration of a subsequent administration unit is not more than 48 hours.
• the time interval is not more than 36 hours, or not more than 24 hours, or not more than 12 hours, or not more than 8 hours, or not more than 6 hours, or not more than 4 hours.
• the administration units are administered on not more than 30 subsequent days.
• the administration units are administered on not more than 25 subsequent days, or on not more than 20 subsequent days, or on not more than 14 subsequent days, or on not more than 10 subsequent days, or on not more than 7 subsequent days, or on not more than 3 subsequent days.
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, is 0.0001 mg/kg body weight to 100 mg/kg body weight.
• the administered daily dose of (i) ⁇ drug 1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5), (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 0.0001 mg/kg body weight to 0.0003 mg/kg body weight, or 0.0003 mg/kg body weight to 0.0005 mg/kg body weight, or 0.0005 mg/kg body weight to 0.001 mg/kg body weight, or 0.001 mg/kg body weight to 0.0025 mg/kg body weight, or 0.0025 mg/kg body weight to 0.005 mg/kg body weight, or 0.005 mg/kg body weight to 0.01 mg/kg body weight, or 0.01 mg/kg body weight to 0.025 mg/kg body weight, or 0.025 mg/kg body weight to 0.05 mg/kg body weight, or 0.05 mg/kg body weight to 0.1 mg/kg body weight,
• the administered daily dose of (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively, is 0.001 mg to 5000 mg.
• the administered daily dose of (i) ⁇ drug 1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively is 0.001 mg to 0.003 mg, or 0.003 mg to 0.005 mg, or 0.005 mg to 0.01 mg, or 0.01 mg to 0.025 mg, or 0.025 mg to 0.05 mg, or 0.05 mg to 0.1 mg, or 0.1 mg to 0.25 mg, or 0.25 mg to 0.5 mg, or 0.5 mg to 1 mg, or 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 10 mg, or 10 mg to 25 mg, or 25 mg to 50 mg, or 50 mg to 100 mg, or 100 mg to 250 mg, or 250 mg to 500 mg, or 500 mg to 1000 mg, or 1000 mg to 1250 mg, or 1250 mg to 1500 mg
• the packaging according to the invention does not comprise any administration unit comprising an active pharmaceutical ingredient other than (i) ⁇ drug1 ⁇ , (ii) ⁇ drug2+drug3 ⁇ , (iii) ⁇ drug4 ⁇ , (iv) ⁇ drug5 ⁇ , (v) ⁇ drug6 ⁇ , (vi) ⁇ drug7 ⁇ , or (vii) ⁇ drug8 ⁇ , respectively.
• the invention also relates to a method for manufacturing an administration unit according to the invention or a packaging according to the invention, comprising the steps:
• step (a) the quantity of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇
• the invention also relates to particles of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug6b ⁇ ; (vi) ⁇ d
• a particle size distribution (preferably by volume) such that at least 90 % of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug
• a particle size distribution (preferably by volume) such that at least 50 % of (i) ⁇ drug1a ⁇ , ⁇ drug1b ⁇ , ⁇ drug1c ⁇ , ⁇ drug1d ⁇ , ⁇ drug1e ⁇ , or ⁇ drug1f ⁇ ; (ii) ⁇ drug2a+drug3a ⁇ or ⁇ drug2a+drug3b ⁇ ; (iii) ⁇ drug4a ⁇ , ⁇ drug4b ⁇ , ⁇ drug4c ⁇ , ⁇ drug4d ⁇ , ⁇ drug4e ⁇ , ⁇ drug4f ⁇ , ⁇ drug4g ⁇ , or ⁇ drug4h ⁇ ; (iv) ⁇ drug5a ⁇ , ⁇ drug5b ⁇ , ⁇ drug5c ⁇ , ⁇ drug5d ⁇ , ⁇ drug5e ⁇ , ⁇ drug5f ⁇ , ⁇ drug5g ⁇ , or ⁇ drug5h ⁇ ; (v) ⁇ drug6a ⁇ or ⁇ drug
• the indicated particle size properties are determined by laser-diffraction method, in particular low angle laser light scattering, i.e. Fraunhofer diffraction.
• the particle size properties can be also determined by microscopy (e.g. electron microscopy or scanning electron microscopy).
• the powder fineness is preferably determined in accordance with USP35 ⁇ 811>. The results of the particle size distribution determined by different techniques can be correlated with one another.
• Suitable milling and grinding techniques that are suitable for obtaining a specific particle size distribution are known to the skilled artisan (see e.g. N. Rasenack, B.W. Müller, Micron-size drug particles: common and novel micronization techniques, Pharm Dev Technol., 2004, 9(1):1-13 ; A. Martin, M.J. Cocero, Micronization processes with supercritical fluids: fundamentals and mechanisms, Adv Drug Deliv Rev. 2008, 60(3):339-50 ; S.C. Gad, Pharmaceutical Manufacturing Handbook: Production and Processes (Pharmaceutical Development Series), Wiley Interscience, 1st ed. 2008 ; A.J. Hickey, Pharmaceutical Process Engineering (Drugs and the Pharmaceutical Sciences), Informa Healthcare, 2nd ed.

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